Brain-derived neurotrophic factor and neuropsychiatric disorders

Abstract

Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development.

Fig. 1.

Overview of BDNF signaling through TrkB receptors. Upon binding to BDNF, the receptor tyrosine kinase TrkB becomes phosphorylated. Phosphorylation at various sites leads to activation of downstream pathways. The PI3K pathway activates protein kinase B (AKT), leading to cell survival. The MAPK/ERK pathway leads to cell growth and differentiation. The PLCγ pathway activates inositol trisphosphate (IP3) receptor to release intracellular calcium stores leading to enhanced calmodulin kinase (CamK) activity, leading to synaptic plasticity. All three pathways converge on transcription factor CREB, which can up-regulate gene expression. DAG, diacylglycerol.

Fig. 2.

Schematic of the role of BDNF in “depression” neurocircuitry. A, depiction of serotonergic, GABAergic, and glutamatergic projection neurons in regions of interest in MDD, including hippocampus (HC), dorsal raphe nucleus (DRN), cortex (PFC), amygdala (AMY), VTA, NAc, and hypothalamus (HYP). B, schematic of BDNF mRNA or protein regulation by depression either from studies of patients with MDD or from studies of animal models of stress. BDNF is down-regulated by MDD or stress in the hippocampus and cortex but increased by these stimuli in the nucleus accumbens and amygdala.

Fig. 3.

Schematic of the role of BDNF in neurocircuitry associated with schizophrenia. A, nearly all neurotransmitter systems, including GABA, serotonin, glutamate, and dopamine, have been implicated in the pathophysiology of schizophrenia. HC, hippocampus; DRN, dorsal raphe nucleus: PFC, cortex; AMY, amygdala; HYP, hypothalamus; VP, ventral palladium; TH, tyrosine hydroxylase. B, studies have produced conflicting evidence on the regulation of BDNF and TrkB in patients with schizophrenia; some reports indicate that BDNF signaling is decreased in the cortex and hippocampus, whereas other reports show opposite results.

Fig. 4.

Schematic of the role of BDNF in the brain reward pathway associated with addiction. A, the brain reward pathway consists of the mesolimbic dopaminergic pathway that projects from the VTA to the NAc. The NAc also receives excitatory input from limbic regions, including the cortex, hippocampus, and amygdala. The NAc in turn sends GABAergic projections to the thalamus via the “direct” and “indirect” pathways. B, addictional research demonstrates that BDNF and TrkB signaling are enhanced in the NAc. Although BDNF mRNA levels are typically low in this area, BDNF may be secreted from limbic regions as well as the VTA. [Adapted from Bolaños CA and Nestler EJ (2004) Neurotrophic mechanisms in drug addiction. Neuromolecular Med 5:69–83. Copyright © 2004 Springer. Used with permission.]